Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A 2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A 1 receptors. Gain of function of the excitatory A 2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A 2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/ CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A 2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A 2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No colocalization was observed between the A 2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A 2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A 2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients. • Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A 2A receptors in astrocytes of the human hippocampus.
Keywords Mesial temporal lobe epilepsy (MTLE• Up-regulation of A 2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.• Targeting astrocytic A 2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.• Inhibitors of astrocytic A 2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.